The invention relates to the field of therapeutic antigenic compounds that are useful to modulate an antigen-specific immune response.
The recognition of antigenic epitopes presented by molecules of the Major Histocompatibility Complex (MHC) plays a central role in the establishment, maintenance and execution of mammalian immune responses. T cell surveillance and recognition of peptide antigens presented by cell surface MHC molecules expressed by somatic cells and antigen presenting leukocytes functions to control invasion by infectious organisms such as viruses, bacteria, and parasites. In addition it has now been demonstrated that antigen specific cytotoxic T lymphocytes (CTL""s) can recognize certain cancer cell antigens and attack cells expressing these antigens. This T cell activity provides a basis for developing novel strategies for anti-cancer vaccines. Furthermore, inappropriate T cell activation plays a central role in a certain debilitating autoimmune diseases such as rheumatoid arthritis, multiple sclerosis, and asthma. Thus presentation and recognition of antigenic epitopes presented by MHC molecules plays a central role in mediating immune responses in multiple pathological conditions.
The ability of a particular peptide to function as a T cell epitope requires that it bind effectively to the antigen presenting domain of an MHC molecule and also that it display an appropriate set of amino acids that can be specifically recognized by a T cell receptor molecule. While it is possible to identify natural T cell epitopes derived from antigenic polypeptides, these peptide epitopes do not necessarily represent antigens that are optimized for inducing a particular immune response. In fact, it has been shown that it is possible to improve the effectiveness of natural epitopes by introducing single N multiple amino acids substitutions that alter their sequence (Valmori et al., 2000. J. Immunol 164(2): 1125-1131). Thus, delivery of carefully optimized synthetic peptide epitopes has the potential to provide an improved method to induce a useful immune response.
The introduction into an animal of an antigen has been widely used for the purposes of modulating the immune response, or lack thereof, to the antigen for a variety of purposes. These include vaccination against pathogens, induction of an immune response to a cancerous cell, reduction of an allergic response, reduction of an immune response to a self antigen that occurs as a result of an autoimmune disorder, reduction of allograft rejection, and induction of an immune response to a self antigen for the purpose of contraception.
Enhancement of the speed and affinity of an immune response to a foreign antigen is the basis of vaccination protocols in which a killed, or live attenuated pathogen, or an antigenic part of a pathogen, is introduced into an individual. One significant disadvantage of such vaccines is that they pose an inherent threat that the virus is not sufficiently attenuated or killed. There is thus the potential for the vaccine to cause the disease against which protection is sought.
In the treatment of cancer, a variety of immunotherapeutic approaches have been taken to generate populations of cytotoxic T lymphocytes which specifically recognize and lyse tumor cells. Many of these approaches depend in part on identifying and characterizing tumor-specific antigens.
More recently, certain pathogen- and tumor-related proteins have been immunologically mimicked with synthetic peptides whose amino acid sequence corresponds to that of an antigenic determinant domain of the pathogen- or tumor-related protein. Despite these advances, peptide immunogens based on native sequences generally perform less than optimally with respect to inducing an immune response. Thus, a need exists for modified synthetic antigenic peptide epitopes with enhanced immunomodulatory properties. This invention satisfies this need and provides related advantages as well.
The present invention provides novel, synthetic compounds that are useful in a variety of methods of modulating an immune response to the synthetic and naturally occurring compounds.
Further provided are polynucleotides encoding the therapeutic compounds, gene delivery vehicles comprising these polynucleotides and host cells comprising these polynucleotides.
In addition, the invention provides methods for inducing an immune response in a subject comprising delivering the compositions of the invention, and delivering the peptide compositions of the invention in the context of an MHC molecule.
The peptides of the invention are useful to generate antibodies that specifically recognize and bind to these molecules. These antibodies are further useful for immunotherapy when administered to a subject.
The invention also provides immune effector cells raised in the presence and at the expense of an antigen presenting cell that presents the peptide compositions of the invention in the context of an MHC molecule and a method of adoptive immunotherapy comprising administering an effective amount of these immune effector cells to a subject.
SEQ ID NO:1. The complete nucleotide sequence of a cDNA encoding the human tyrosine kinase-type receptor HER2. The coding region extends from position 151 through position 3918.
SEQ ID NO:2. The amino acid sequence of the native human tyrosine kinase-type receptor HER2. The compounds of the invention are variations based on native HER2 peptide 774-782.
SEQ ID NO:3. The amino acid sequence of compound 1 (FLYYGTTYV).
SEQ ID NO:4. The polynucleotide sequence encoding compound 1.
SEQ ID NO:5. The amino acid sequence of compound 2 (FLFTPTIYV).
SEQ ID NO:6. The polynucleotide sequence encoding compound 2.
SEQ ID NO:7. The amino acid sequence of compound 3 (FLFDPTTYV).
SEQ ID NO:8. The polynucleotide sequence encoding compound 3.